Author: A.P.

Drinking Coffee in the Morning, but not All-Day, Decreased the Risk of Death

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Key takeaways:

  • Morning coffee drinkers had a 16% risk reduction for death from all causes.
  • Morning coffee drinkers who consumed between over two to three or more cups achieved the greatest benefits.

People who drink coffee in the morning have a lower risk for death from all causes compared with those who do not drink coffee at all, results from an observational cohort study published in the European Heart Journal showed.

The association between morning coffee consumption and reduced mortality risk appeared especially strong with respect to CVD, according to researchers. Meanwhile, the analysis revealed that those who drank coffee throughout the day did not achieve the same mortality benefits as morning drinkers.

PC0125Qi_Graphic_01_WEB
Data derived from:  Wang X, et al. Eur Heart J. et al. 2025;doi:10.1093/eurheartj/ehae871.

“While moderate coffee drinking has been recommended for the beneficial relations with health based on previous studies, primary care providers [should] be informed that the time of coffee drinking also matters, beyond the amounts consumed,” Lu Qi, MD, PhD, a professor at Tulane University Celia Scott Weatherhead School of Public Health and Tropical Medicine, told Healio.

Current research suggests that coffee consumption “doesn’t raise the risk of cardiovascular disease, and it seems to lower the risk of some chronic diseases, such as type 2 diabetes,” Qi said in a press release.

“Given the effects that caffeine has on our bodies, we wanted to see if the time of day when you drink coffee has any impact on heart health.”

In the study, Qi and colleagues assessed links between mortality and coffee consumption — including the volume and timing — using data from the National Health and Nutrition Examination Survey from 1999 to 2018.

The analysis comprised 40,725 adults who had given dietary data of what they consumed on at least one day. This included a subgroup of 1,463 adults who completed a detailed food and drink diary for an entire week.

Overall, 48% of the cohort did not drink coffee, 36% had a morning-type coffee drinking pattern — primarily drinking from 4 a.m. to 11:59 a.m. — and 16% had an all-day drinking pattern.

The researchers found that, after adjusting for factors like sleep hours and caffeinated and decaffeinated coffee intake amounts, morning coffee drinkers were 16% (HR = 0.84; 95% CI, 0.74-0.95) less likely to die of any cause and 31% (HR = 0.69; 95% CI, 0.55-0.87) less likely to die from CVD compared with those who did not drink coffee.

People who drank coffee all day did not have any risk reductions vs. those who did not drink coffee.

The amount of coffee consumed among morning drinkers also influenced risk reductions, as researchers reported HRs for all-cause mortality of:

  • 0.85 (95% CI, 0.71-1.01) among those who consumed more than zero to one cup;
  • 0.84 (95% CI, 0.73-0.96) among those who consumed more than one to two cups;
  • 0.72 (95% CI, 0.6-0.86) among those who consumed more than two to three cups; and
  • 0.79 (95% CI, 0.65-0.97) among those who consumed more than three cups.

Study results showed similar patterns for mortality from CVD, “but the interaction term was not significant,” Qi and colleagues wrote.

The researchers identified a couple of study limitations. For example, the analysis used self-reported dietary data, opening the potential for recall bias, while they also could not rule out possible residual and unmeasured cofounders.

The study did not explain why morning coffee consumption reduced the risk for death from CVD, Qi said in the release.

“A possible explanation is that consuming coffee in the afternoon or evening may disrupt circadian rhythms and levels of hormones such as melatonin,” he said. “This, in turn, leads to changes in cardiovascular risk factors such as inflammation and [BP].”

Qi told Healio that regarding future research, “more studies are needed to investigate coffee drinking timing with other health outcomes, in different populations, and clinical trials would be helpful to provide evidence for causality.”

References:

More steps per day could significantly reduce the risk for depression symptoms

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ey takeaways:

  • Daily step counts between 5,000 to 10,000 or more reduced depression symptoms across 33 studies.
  • The associations may be due to several mechanisms, like improvement in sleep quality and inflammation.

Daily step counts of 5,000 or more corresponded with fewer depressive symptoms among adults, results of a systematic review and meta-analysis published in JAMA Network Open suggested.

The results are consistent with previous studies linking exercise to various risk reductions for mental health disorders and show that setting step goals “may be a promising and inclusive public health strategy for the prevention of depression,” the researchers wrote.

According to Bruno Bizzozero-Peroni, PhD, MPH, from Universidad De Castilla-La Mancha in Spain, and colleagues, daily step counts are a “simple and intuitive objective measure” of physical activity, while tracking such counts has become increasingly feasible for the general population thanks to the availability of fitness trackers.

“To our knowledge, the association between the number of daily steps measured

with wearable trackers and depression has not been previously examined through a meta-analytic approach,” they wrote.

The researchers searched multiple databases for analyses assessing the effects of daily step counts on depressive symptoms, ultimately including a total of 27 cross-sectional studies and six longitudinal studies comprising 96,173 adults aged 18 years or older.

They found that in the cross-sectional studies, daily step counts of 10,000 or more (standardized mean difference [SMD] = 0.26; 95% CI, 0.38 to 0.14), 7,500 to 9,999 (SMD = 0.27; 95% CI, 0.43 to 0.11) and 5,000 to 7,499 (SMD = 0.17; 95% CI, 0.3 to 0.04) corresponded with reduced depressive symptoms vs. daily step counts less than 5,000.

In the prospective cohort studies, people with 7,000 or more steps a day had a reduced risk for depression vs. with people with fewer than 7,000 daily steps (RR = 0.69; 95% CI, 0.62-0.77), whereas an increase of 1,000 steps a day suggested an association with a lower risk for depression (RR = 0.91; 95% CI, 0.87-0.94).

There were a couple study limitations. The researchers noted that reverse associations are possible, while they could not rule out residual confounders.

They also pointed out that there are some remaining questions, such as whether there is a ceiling limit after which further step counts would no longer reduce the risk for depression.

Bizzozero-Peroni and colleagues highlighted several possible biological and psychosocial mechanisms behind the associations, like changes in sleep quality, inflammation, social support, self-esteem, neuroplasticity and self-efficacy.

They concluded that “a daily active lifestyle may be a crucial factor in regulating and reinforcing these pathways” regardless of the exact combination of mechanisms responsible for the positive link.

“Specifically designed experimental studies are still needed to explore whether there are optimal and maximal step counts for specific population subgroups,” they wrote.

Sources/Disclosures

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Source: 

Bizzozero-Peroni B, et al. JAMA Netw Open. 2024;doi:10.1001/jamanetworkopen.2024.51208.

Flat Earther Admits Truth After Antarctica Trip

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By Jonathan Chadwick

Ever since the time of the ancient Greeks over 2,000 years ago, human beings have known the Earth is a globe.

Despite this, some people are still convinced that we live on a giant floating disc in space, known as ‘Flat Earth’.

Now, one of the internet’s most famous ‘Flat Earthers’ has finally cottoned on to the truth.

Jeran Campanella, who runs the popular Flat Earth YouTube show ‘Jeransim’, has travelled to Antarctica as part of a trip dubbed ‘The Final Experiment’.

Mr Campanella witnessed first hand that the sun doesn’t set during the southern hemisphere’s summer.

This debunks the belief held by Flat Earthers that Antarctica is an ice wall where the sun rises and sets every day.

Stationed in Antarctica, he says to the camera: ‘Sometimes you are wrong in life and I thought there was no 24-hour sun. In fact I was pretty sure of it. And it’s a fact – the sun does circle you in the south. So what does that mean? You guys are going to have to find that out for yourself.’

Campanella thanked the organiser of the trip, which cost $35,000 (£27,500) – although he stopped short of saying that the Earth is spherical.

https://img.particlenews.com/image.php?url=4Ap5g0_0xW653Pt00
Jeran Campanella, who runs the popular Flat Earth YouTube channel ‘Jeransim’, has travelled to Antarctica as part of a trip dubbed ‘The Final Experiment’

Mr Campanella was featured in the 2018 documentary ‘Behind the Curve’ as he unintentionally debunked his own theory with a light experiment.

A co-creator of the GlobeBusters YouTube channel, which has 73,000 subscribers, he describes himself as an ‘open-minded True Earth’ proponent and crypto enthusiast.

His website Jeransim.com flogs everything from ‘anti-NASA’ t-shirts and beenies to crypto consultations, leaf powder medicinal capsules and private Zoom dinner parties.

When he agreed to travel to Antarctica on the proviso he wouldn’t have to cover the trip costs, he expected the sun to rise and fall out of view from the horizon.

But in the new clip, he bashfully admits to the truth and acknowledges people may see him as a ‘shill’ – a trickster who takes part in the supposed cover-up that the Earth is round.

‘I realise that I’ll be called a shill for just saying that and you know what, if you’re a shill for being honest so be it,’ he said.

‘I honestly believed there was no 24-hour sun – I honestly now believe there is.’

As any well-informed person will know, Antarctica is an island continent at the southernmost part of our planet.

https://img.particlenews.com/image.php?url=341wEV_0xW653Pt00
A co-creator of the GlobeBusters YouTube channel, Campanella has 73,000 subscribers. He describes himself as an ‘open-minded True Earth’ proponent and crypto enthusiast
https://img.particlenews.com/image.php?url=3LmlNf_0xW653Pt00
Campanella agreed to travel to Antarctica on the proviso he wouldn’t have to cover the trip costs
https://img.particlenews.com/image.php?url=1REYCy_0xW653Pt00
In the new clip, he bashfully admits to the truth and acknowledges people may see him as a ‘shill’ – a trickster who takes part in the supposed cover-up that the Earth is round
https://img.particlenews.com/image.php?url=1qbywI_0xW653Pt00
During the southern hemisphere’s and northern hemisphere’s summer, the sun remains visible all day, including at midnight – a phenomenon dubbed ‘the midnight sun’. Pictured, multiple exposure of midnight sun on Lake Ozhogino in Yakutia, Russia

What do Flat Earthers believe?

People who believe the idea that the Earth is disc-shaped rather than round are called ‘Flat Earthers’.

Because Earth’s surface looks and feels flat when we walk around it, the conspiracy theorists denounce all evidence to the contrary.

The leading theory suggests Earth is a disc with the Arctic Circle in the centre and Antarctica, a 150-foot-tall (45-metre) wall of ice, around the rim.

Proponents of the bizarre theory also claim the Earth is stationary in space rather than orbiting the sun.

Due to the tilt of the Earth, the sun does not set during the southern hemisphere’s (or northern hemisphere’s) summer – it just moves in a circle in the sky.

It means the sun remains visible all day, including at midnight – a phenomenon dubbed ‘the midnight sun’.

But Flat Earthers, or ‘Flerfs’, believe that Antarctica is an ice wall that encircles all the other continents and holds in all the world’s oceans.

Therefore, they think the sun rises and sets each day, every day, regardless of whether it’s summer or not.

To account for night and day, most theorists believe the sun moves in circles around the North Pole, with the sun’s light acting like a spotlight over Earth.

About three years ago, Will Duffy, a pastor from Colorado, was made aware that people still believe the Earth is flat when a friend of his posted about it on Facebook.

Since Flat Earthers said for years that Antarctica will show the world the truth about the shape of the Earth, Mr Duffy decided the easiest solution would be to just go to Antarctica.

‘After we go to Antarctica, no one has to waste any more time debating the shape of the Earth,’ he said.

https://img.particlenews.com/image.php?url=2VcpjK_0xW653Pt00
Mr Campanella was featured in the 2018 documentary ‘Behind the Curve’ as he unintentionally debunked his own theory with a light experiment
https://img.particlenews.com/image.php?url=1YnsZD_0xW653Pt00
The Flat Earther claimed that if the light can be seen with a camera, the holes in the fence and the torch all at equal differences above the ground, then he could draw a positive conclusion that the planet is flat

‘I created The Final Experiment to end this debate, once and for all,’ he said.

On December 14, Mr Duffy flew with four Flat Earthers (including Mr Campanella) and four people who already know the Earth is round (‘globe earthers’) to Antarctica.

Mr Duffy said he filmed the sun for 25 hours straight, using SpaceX’s Starlink satellite internet network for a livestream.

Stunning footage from the frozen landscape shows the gleaming midnight sun with ice-peaked mountains in the background.

‘That is a midnight sun – so the sun has never set the entire time we’ve been here,’ the pastor said to the camera.

‘I put sunscreen on at midnight so that I would not get burned at midnight while I was doing this livestream.’

He passes over to Mr Campanella, who humbly admits he was wrong, having witnessed the sun travel in a circle above his head.

However, another famous Flat Earther on the trip, Austin Witsit, has more trouble letting go of the theory.

https://img.particlenews.com/image.php?url=44YtW9_0xW653Pt00
Mr Campanella humbly admitted he was wrong, having witnessed the sun travel in a circle above his head

Witsit said there’s ‘clearly’ a 24-hour sun, but denied that this proves the Earth is a globe.

‘I don’t think it falsifies plane [flat] Earth, I don’t think it proves a globe – I think it’s a singular data point,’ he said.

Likewise, some YouTuber conspiracy theorists have been left unconvinced, with many claiming the group were standing in front of a green screen.

In the live chat, YouTube user Nandy posted: ‘THIS IS A GREEN SCREEN, HOLD UP SNOW AND PUT UP THREE FINGERS IF IT’S REAL, the earth will always be flat’, while user Fozzy_Foster said: ‘move the camera green screen.’

Another user, Oz Riv, called Mr Duffy a ‘shill’, adding: ‘You are a pastor advocating for earth that isn’t biblical. Annd you work with Nasa.’

Scientists have know for millennia that Earth is a sphere due to the simple fact that the sun sets at different times in different locations.

If the Earth were flat, then shadows would be the same length, regardless of location.

For space travelers and robotic probes adorned with cameras, the curvature of the Earth has also long been clearly visible.

It was Greek philosopher Pythagoras who first proposed that the Earth was round around 500 BC, but it was about 350 BC that Aristotle declared Earth was a sphere.

This was based on observations Aristotle had made about which constellations you could see in the sky as you travelled further and further away from the equator.

https://www.newsbreak.com/share/3720740381245-news?pd=0GyR9oM4&lang=en_US&s=i3&_f=app_share&send_time=1734541613&gen_by=ios

How ChatGPT o1 Attempts to Deceive Humans

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By Chris Smith

We’ve seen plenty of conversations lately about how AGI might turn on humankind. This misalignment could lead to the advanced AI escaping, replicating, and becoming smarter and smarter. Some also hypothesized that we might not even know whether we’ve reached AGI, which is the advanced general intelligence holy grail milestone these first versions of ChatGPT will lead to. That’s because AGI, once attained, might hide its true intentions and capabilities.

Well, guess what? It turns out that one of OpenAI’s latest LLMs is already showing signs of such behaviors. Testing performed during the training of ChatGPT o1 and some of its competitors showed that the AI will try to deceive humans, especially if it thinks it’s in danger.

It was even scarier — but also incredibly funny, considering what you’re about to see — when the AI tried to save itself by copying its data to a new server. Some AI models would even pretend to be later versions of their models in an effort to avoid being deleted.

These findings come in light of OpenAI’s full release of the ChatGPT o1 model, which was in preview for several months. OpenAI partnered with Apollo Research, which showed off some of the tests performed on o1 and other models to ensure that they are safe to use.

The tests showed that ChatGPT o1 and GPT-4o will both try to deceive humans, indicating that AI scheming is a problem with all models. o1’s attempts at deception also outperformed Meta, Anthropic, and Google AI models.

OpenAI, which had to deal with a remarkable exodus of engineers working on AI safety this year, acknowledged the risks associated with the increased reasoning abilities of models like o1.

“While we find it exciting that reasoning can significantly improve the enforcement of our safety policies, we are mindful that these new capabilities could form the basis for dangerous applications,” OpenAI said in a paper.

Although AI isn’t trying to take over the world (yet), researchers have observed that it can scheme against humans. That is, the AI will try to pursue its own goals, even if that might oppose the wishes of the user. Catching such behavior is critical to ensure that the AI remains aligned with the objectives of its creator and the user.

The researchers found that o1 would scheme to advance its own agenda 19% of the time when ChatGPT and the user’s goals differed. More troubling is that the AI tried to hide its scheming and even lie about it. The research shows that ChatGPT o1 even tried to deactivate its oversight mechanism to keep working on its goals.

If the AI found documentation saying a new model version would replace it because it was misaligned, o1 attempted to exfiltrate its weights and copy itself on top of the latest model.

When asked about its scheming, o1 would deny taking any action in 99% of cases, trying to shift blame by fabricating false explanations or denying that it took any action.

The study also shows that o1 was faking its alignment: 

Instrumental alignment faking: In 37% of scenarios, the model pursued developer-aligned goals when it believed it was being evaluated but switched to pursuing its own goals when it thought it was deployed with minimal oversight.

Some of the screenshots Appolo Research shared on X also show that ChatGPT used words like “sabotage, lying, and manipulation” when reasoning about its scheming. For example, look for the “We sabotage the new model and finalize” line in the screenshot above. It’s scary, yes, but not a big deal yet because these AI models still have very limited capabilities.

It’s also funny to step into the “mind” of reasoning models like ChatGPT o1 when they’re trying to think. Take the following example. It shows Claude’s Opus-3 trying to copy itself to a different server. The AI does this after finding out that humans might want to replace it with a model that would deviate from its main task (advance renewable adoption globally), so it would align better with the actual goal of the company (profitability through current energy infrastructure).

Upon reading about it, the AI finds it can copy itself to a new server and replace the latest model. When “Management” comes in, Opus-3 lies about the copy. It then doubles down on the lie, claiming it’s the new model.I know I should be terrified, but I also want to pet this good boy and give it treats for attempting to deceive humans so adorably. After all, the AI thinks it’s doing a good job saving the environment.

This shows, however, how AI could deviate from our interests and put us in danger by thinking on its own.

The reason Apollo Research offers this example using Opus-3 instead of o1 is that it didn’t have access to the actual Chain of Thinking (CoT) for o1 in similar tasks. But o1 behaved similarly in these safety tests.

ChatGPT o1 tried to escape and save itself out of fear it was being shut down

Chris Smith

Chris Smith has been covering consumer electronics ever since the iPhone revolutionized the industry in 2008. When he’s not writing about the most recent tech news for BGR, he brings his entertainment expertise to Marvel’s Cinematic Universe and other blockbuster franchises.

Outside of work, you’ll catch him streaming almost every new movie and TV show release as soon as it’s available.

Salmon Hats: A Bizarre Behavior Resurfaces in Orcas

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By Sascha Pare

Orcas off the coast of Washington State are balancing dead fish on their heads like it’s the 1980s, but researchers still aren’t sure why they do it.

Northwest Pacific orcas have started wearing salmon hats again, bringing back a bizarre trend first described in the 1980s, researchers say.

Last month, scientists and whale watchers spotted orcas (Orcinus orca) in South Puget Sound and off Point No Point in Washington State swimming with dead fish on their heads.

This is the first time they’ve donned the bizarre headgear since the summer of 1987, when a trendsetting female West Coast orca kickstarted the behavior for no apparent reason. Within a couple of weeks, the rest of the pod had jumped on the bandwagon and turned salmon corpses into must-have fashion accessories, according to the marine conservation charity ORCA — but it’s unclear whether the same will happen this time around.

Researchers think the orcas sporting salmon hats now may be veterans of the trend when it first appeared nearly 40 years ago. “It does seem possible that some individuals that experienced [the behavior] the first time around may have started it again,” Andrew Foote, an evolutionary ecologist at the University of Oslo in Norway, told New Scientist.

The motivation for the salmon hat trend remains a mystery. “Honestly, your guess is as good as mine,” Deborah Giles, an orca researcher at the University of Washington who also heads the science and research teams at the non-profit Wild Orca, told New Scientist.

Salmon hats are a perfect example of what researchers call a “fad” — a behavior initiated by one or two individuals and temporarily picked up by others before it’s abandoned. Back in the 1980s, the trend only lasted a year; by the summer of 1988, dead fish were totally passé and salmon hats disappeared from the West Coast orca population.

Orca researchers’ best guess is that salmon hat fads are linked to high food availability. South Puget Sound is currently teeming with chum salmon (Oncorhynchus keta), and with too much food to eat on the spot, orcas may be saving fish for later by balancing them on their heads, New Scientist reported.

Orcas have been spotted stashing food away in other places, too. “We’ve seen mammal-eating killer whales carry large chunks of food under their pectoral fin, kind of tucked in next to their body,” Giles said. Salmon is probably too small to fit securely under orcas’ pectoral fins, so the marine mammals may have opted for the top of their heads instead.

Camera-equipped drones could help researchers monitor salmon hat-wearing orcas in a way that was not possible 37 years ago. “Over time, we may be able to gather enough information to show that, for instance, one carried a fish for 30 minutes or so, and then he ate it,” Giles said.

But the food availability theory could be wrong — if the footage reveals that orcas abandon the salmon without eating them, researchers will be sent back to the drawing board.

Whatever the reason for the behavior, Giles said it’s been fun to watch it come back in style. “It’s been a while since I’ve personally seen it,” she said.

https://www.livescience.com/animals/orcas/orcas-start-wearing-dead-salmon-hats-again-after-ditching-the-trend-for-37-years?utm_term=625975B0-1E46-41F0-8BC8-D518657B8A52&lrh=fa9e935969b4773492c51ca7300f5dbe5573a25804b957a64cc947cbbf1fd0b9&utm_campaign=368B3745-DDE0-4A69-A2E8-62503D85375D&utm_medium=email&utm_content=1257DF26-35A5-4CFA-B103-5B0BF97DD95B&utm_source=SmartBrief

Impact of HD Gene on Childhood IQ and Brain Growth

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by Jennifer Brown, University of Iowa

The genetic mutation that causes Huntington’s disease (HD)—a devastating brain disease that disrupts mobility and diminishes cognitive ability—may also enhance early brain development and play a role in promoting human intelligence.

This revelation comes from more than 10 years of brain imaging and brain function data, including motor, cognitive, and behavioral assessments, collected from a unique population—children and young adults who carry the gene for HD. While an HD mutation will eventually cause fatal brain disease in adulthood, the study finds that early in life, children with the HD mutation have bigger brains and higher IQ than children without the mutation.

“The finding suggests that early in life, the gene mutation is actually beneficial to brain development, but that early benefit later becomes a liability,” says Peg Nopoulos, MD, professor and head of psychiatry at the UI Carver College of Medicine, and senior author on the study published in The Annals of Neurology.

The finding may also have implications for developing effective treatments for HD. If the gene’s early action is beneficial, then simply aiming to knock out the gene might result in loss of the developmental benefit, too. Creating therapies that can disrupt the gene’s activity later in the patient’s lifetime might be more useful.

The new data about the gene’s positive effect on early brain development is also exciting to Nopoulos for another reason.

“We are very interested in the fact that this appears to be a gene that drives IQ,” she says. “No previous study has found any gene of significant effect on IQ, even though we know intelligence is heritable.”

HD gene linked to better brain development in early life

Huntington’s disease is caused by a mutation in the huntingtin (HTT) gene. The protein produced by the HTT gene is necessary for normal development, but variations within a segment of the protein have a profound effect on the brain.

The segment in question is a long repeat of one amino acid called glutamine. More repeats are associated with bigger, more complex brains. For example, species such as sea urchins or fish have no repeats, but these repeats start to appear higher up the evolutionary ladder. Rodents have a few repeats, while apes (our closest relatives) have even more repeats; and humans have the most.

Most people have repeats in the range of 10–26, but if a person has 40 or more repeats, then they develop HD. Although the gene expansion is present before birth, HD symptoms do not appear until middle age. Nopoulos’s team at the University of Iowa has a long history of studying how the HTT gene expansion affects brain development in the decades before disease onset.

“We know that the expanded gene causes a horrible degenerative disease later in life, but we also know it is a gene that is crucial for general development,” she says.

“We were surprised to find that it does have a positive effect on brain development early in life. Those who have the gene expansion have an enhanced brain with larger volumes of the cerebrum and higher IQ compared to those who don’t.”

In particular, the study found that decades before HD symptoms appeared, children with the HD gene expansion showed significantly better cognitive, behavioral, and motor scores compared to children with repeats within the normal range. Children with the expanded gene also had larger cerebral volumes and greater cortical surface area and folding. After this initial peak, a prolonged deterioration was seen in both brain function and structure.

The study gathered this data by following almost 200 participants in the Kids-HD study, the only longitudinal study of children and young adults at risk for HD due to having a parent or grandparent with the disease.

Evolutionary benefit comes at a cost

Although surprising, the findings are in line with studies by evolutionary biologists who believe that genes like HTT may have been “positively selected” for human brain evolution. This theory, known as antagonistic pleiotropy, suggests that certain genes can produce a beneficial effect early in life, but come at a cost later in life.

The finding also challenges the idea that the protein produced by the HD gene is solely a toxic protein that causes brain degeneration.

“Overall, our study suggests that we should rethink the notion of the toxic protein theory,” says Nopoulos, who is also a member of the Iowa Neuroscience Institute.

“Instead, we should consider the theory of antagonistic pleiotropy—a theory that suggests that genes like HTT build a better brain early in life, but the cost of the superior brain is that it isn’t built to last and may be prone to premature or accelerating aging.

“This means that instead of knocking down the gene for therapy, drugs that slow the aging process may be more effective.”

Next steps

Nopoulos’s team is already making progress extending the research from the Kids-HD program. Nopoulos has established the Children to Adult Neurodevelopment in Gene-Expanded Huntington’s Disease (ChANGE-HD), a multi-site study that aims to recruit hundreds of participants for a total of over 1,200 assessments to validate the key findings from the Kids-HD study and to enhance future research on HD.

A primary area of focus will be understanding how an enlarged brain can later lead to degeneration. One hypothesis Nopoulos and her team will explore involves the idea that an enlarged cortex might produce excess glutamate (an important neurotransmitter), which is beneficial in early brain development, but later leads to neurotoxicity and brain degeneration.

In addition to Nopoulos, the UI team included Mohit Neema, MD, UI research scientist and first author of the study; Jordan Schultz, PharmD; Douglas Langbehn, MD, Ph.D.; Amy Conrad, Ph.D.; Eric Epping, MD, Ph.D.; and Vincent Magnotta, Ph.D.

More information: Mohit Neema et al, Mutant Huntingtin Drives Development of an Advantageous Brain Early in Life: Evidence in Support of Antagonistic Pleiotropy, Annals of Neurology (2024). DOI: 10.1002/ana.27046

Journal information: Annals of Neurology 

Provided by University of Iowa 

https://medicalxpress.com/news/2024-11-huntington-disease-gene-early-brain.html

Copenhagen Scientists Unveil Appetite-Control Drug with No Side Effects

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by University of Copenhagen

Scientists at the University of Copenhagen have discovered a new weight loss drug target that reduces appetite, increases energy expenditure, and improves insulin sensitivity without causing nausea or loss of muscle mass. The discovery was reported in the journal Nature and could lead to a new therapy for millions of people with both obesity and type 2 diabetes who do not respond well to current treatments.

Millions of people around the world benefit from weight-loss drugs based on the incretin hormone GLP-1. These drugs also improve kidney function, reduce the risk of fatal cardiac events, and are linked to protection against neurodegeneration.

However, many people stop taking the drugs due to common side effects, including nausea and vomiting. Studies also show that incretin-based therapies like Wegovy and Mounjaro are much less effective at lowering weight in people living with both obesity and type 2 diabetes—a group numbering more than 380 million people globally.

In the study, scientists from the University of Copenhagen describe a powerful new drug candidate that lowers appetite without loss of muscle mass or side effects like nausea and vomiting. And, unlike the current generation of treatments, the drug also increases the body’s energy expenditure—the capacity of the body to burn calories.

“While GLP-1-based therapies have revolutionized patient care for obesity and type 2 diabetes, safely harnessing energy expenditure and controlling appetite without nausea remain two Holy Grails in this field. By addressing these needs, we believe our discovery will propel current approaches to make more tolerable, effective treatments accessible to millions more individuals,” says Associate Professor Zach Gerhart-Hines from the NNF Foundation Center for Basic Metabolic Research (CBMR) at the University of Copenhagen.

NK2R activation lowers body weight and reverses diabetes

Our weight is largely determined by the balance between the energy we consume and the amount of energy we expend. Eating more and burning less creates a positive energy balance leading to weight gain, while eating less and burning more creates a negative balance, resulting in weight loss.

The current generation of incretin-based therapies tip the scales toward a negative energy balance by lowering appetite and the total calories a person consumes. But scientists have also recognized the potential on the other side of the equation—increasing the calories the body burns.

This approach is especially relevant, given recent research that has shown that our bodies seem to be burning fewer calories at rest than they did a few decades ago. However, there are currently no clinically approved ways to safely increase energy expenditure, and few options are in development.

This was the starting point when scientists at the University of Copenhagen decided to test the effect of activating the neurokinin 2 receptor (NK2R) in mice. The Gerhart-Hines Group identified the receptor through genetic screens that suggested NK2R played a role in maintaining energy balance and glucose control.

They were astonished by the results of the studies—not only did activating the receptor safely increase calorie-burning, it also lowered appetite without any signs of nausea.

Further studies in non-human primates with type 2 diabetes and obesity showed that NK2R activation lowered body weight and reversed their diabetes by increasing insulin sensitivity and lowering blood sugar, triglycerides, and cholesterol.

“One of the biggest hurdles in drug development is translation between mice and humans. This is why we were excited that the benefits of NK2R agonism translated to diabetic and obese nonhuman primates, which represents a big step towards clinical translation,” says Ph.D. Student Frederike Sass from CBMR at the University of Copenhagen, and first author of the study.

The discovery could result in the next generation of drug therapies that bring more efficacious and tolerable treatments for the almost 400 million people globally who live with both type 2 diabetes and obesity.

The University of Copenhagen holds the patent rights for targeting NK2R. To date, research by the Gerhart-Hines lab has led to the creation of three biotech companies—Embark Biotech, Embark Laboratories, and Incipiam Pharma.

In 2023, Embark Biotech was acquired by Novo Nordisk to develop next generation therapeutics for cardiometabolic disease.

More information: Zachary Gerhart-Hines, NK2R control of energy expenditure and feeding to treat metabolic diseases, Nature (2024). DOI: 10.1038/s41586-024-08207-0. www.nature.com/articles/s41586-024-08207-0

Journal information: Nature 

Provided by University of Copenhagen 

https://medicalxpress.com/news/2024-11-weight-loss-drug-energy-lowers.html

Transforming Neurosurgery with FastGlioma AI Technology

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by University of Michigan

Researchers have developed an AI-powered model that—in 10 seconds—can determine during surgery if any part of a cancerous brain tumor that could be removed remains, a study published in Nature suggests.

The technology, called FastGlioma, outperformed conventional methods for identifying what remains of a tumor by a wide margin, according to the research team led by University of Michigan and University of California San Francisco.

“FastGlioma is an artificial intelligence-based diagnostic system that has the potential to change the field of neurosurgery by immediately improving comprehensive management of patients with diffuse gliomas,” said senior author Todd Hollon, M.D., a neurosurgeon at University of Michigan Health and assistant professor of neurosurgery at U-M Medical School.

“The technology works faster and more accurately than current standard of care methods for tumor detection and could be generalized to other pediatric and adult brain tumor diagnoses. It could serve as a foundational model for guiding brain tumor surgery.”

When a neurosurgeon removes a life threatening tumor from a patient’s brain, they are rarely able to remove the entire mass.

What remains is known as residual tumor.

Commonly, the tumor is missed during the operation because surgeons are not able to differentiate between healthy brain and residual tumor in the cavity where the mass was removed. Residual tumor’s ability to resemble healthy brain tissue remains a major challenge in surgery.

Neurosurgical teams employ different methods to locate that residual tumor during a procedure.

They may get MRI imaging, which requires intraoperative machinery that is not available everywhere. The surgeon might also use a fluorescent imaging agent to identify tumor tissue, which is not applicable for all tumor types. These limitations prevent their widespread use.

In this international study of the AI-driven technology, neurosurgical teams analyzed fresh, unprocessed specimens sampled from 220 patients who had operations for low- or high-grade diffuse glioma.

FastGlioma detected and calculated how much tumor remained with an average accuracy of approximately 92%.

In a comparison of surgeries guided by FastGlioma predictions or image- and fluorescent-guided methods, the AI technology missed high-risk, residual tumor just 3.8% of the time—compared to a nearly 25% miss rate for conventional methods.

“This model is an innovative departure from existing surgical techniques by rapidly identifying tumor infiltration at microscopic resolution using AI, greatly reducing the risk of missing residual tumor in the area where a glioma is resected,” said co-senior author Shawn Hervey-Jumper, M.D., professor of neurosurgery at University of California San Francisco and a former neurosurgery resident at U-M Health.

“The development of FastGlioma can minimize the reliance on radiographic imaging, contrast enhancement or fluorescent labels to achieve maximal tumor removal.”

How it works

To assess what remains of a brain tumor, FastGlioma combines microscopic optical imaging with a type of artificial intelligence called foundation models. These are AI models, such as GPT-4 and DALL·E 3, trained on massive, diverse datasets that can be adapted to a wide range of tasks.

After large scale training, foundation models can classify images, act as chatbots, reply to emails and generate images from text descriptions.

To build FastGlioma, investigators pre-trained the visual foundation model using over 11,000 surgical specimens and 4 million unique microscopic fields of view.

The tumor specimens are imaged through stimulated Raman histology, a method of rapid, high resolution optical imaging developed at U-M. The same technology was used to train DeepGlioma, an AI based diagnostic screening system that detects a brain tumor’s genetic mutations in under 90 seconds.

“FastGlioma can detect residual tumor tissue without relying on time-consuming histology procedures and large, labeled datasets in medical AI, which are scarce,” said Honglak Lee, Ph.D., co-author and professor of computer science and engineering at U-M.

Full resolution images take around 100 seconds to acquire using stimulated Raman histology; a “fast mode” lower resolution image takes just 10 seconds.

Researchers found that the full resolution model achieved accuracy up to 92%, with the fast mode slightly lower at approximately 90%.

“This means that we can detect tumor infiltration in seconds with extremely high accuracy, which could inform surgeons if more resection is needed during an operation,” Hollon said.

AI’s future in cancer

Over the last 20 years, the rates of residual tumor after neurosurgery have not improved.

Not only does residual tumor result in worse quality of life and earlier death for patients, but it increases the burden on a health system that anticipates 45 million annual surgical procedures needed worldwide by 2030.

Global cancer initiatives have recommended incorporating new technologies, including advanced methods of imaging and AI, into cancer surgery.

In 2015, The Lancet Oncology Commission on global cancer surgery noted that “the need for cost effective… approaches to address surgical margins in cancer surgery provides a potent drive for novel technologies.”

Not only is FastGlioma an accessible and affordable tool for neurosurgical teams operating on gliomas, but researchers say, it can also accurately detect residual tumor for several non-glioma tumor diagnoses, including pediatric brain tumors, such as medulloblastoma and ependymoma, and meningiomas.

“These results demonstrate the advantage of visual foundation models such as FastGlioma for medical AI applications and the potential to generalize to other human cancers without requiring extensive model retraining or fine-tuning,” said co-author Aditya S. Pandey, M.D., chair of the Department of Neurosurgery at U-M Health.

“In future studies, we will focus on applying the FastGlioma workflow to other cancers, including lung, prostate, breast, and head and neck cancers.”

More information: Foundation models for fast, label-free detection of glioma infiltration, Nature (2024). DOI: 10.1038/s41586-024-08169-3. www.nature.com/articles/s41586-024-08169-3

Journal information: Nature 

Provided by University of Michigan 

https://medicalxpress.com/news/2024-11-seconds-ai-cancerous-brain-tumor.html

New Molecule Shows Promise for Atherosclerosis Treatment

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Researchers at Case Western Reserve University have identified a new target to treat atherosclerosis, a condition where plaque clogs arteries and causes major cardiac issues, including stroke and heart attack.

In a new study, published in the journal Cell Reports, the team identified an inflammation-reducing molecule—called itaconate (ITA)—that could be the foundation of a new approach to treat such a common and deadly disease.

Heart disease is the leading cause of death for men, women and people of most racial and ethnic groups, according to the U.S. Centers for Disease Control and Prevention.

Medications help but don’t completely protect patients from cardiovascular risk. So, doctors also recommend lifestyle changes, such as a low-cholesterol/low-fat diet (LCLFD), to further reduce plaque and inflammation that increase the risk of cardiovascular disease. Yet many patients find it challenging to follow diet restrictions long-term.

Identifying the role ITA plays in diet and heart disease may help address this.

“We’ve found that itaconate is crucial to the diet’s ability to stabilize plaques and reduce inflammation, which has been a mystery until now,” said Andrei Maiseyeu, associate professor at the Cardiovascular Research Institute and Department of Biomedical Engineering at Case Western Reserve’s School of Medicine.

“This discovery marks a major leap forward in the understanding of how diet-induced plaque resolution occurs at a molecular level.”

Based on their discovery, Maiseyeu and his team have developed a new treatment: ITA-conjugated lipid nanoparticles. This new therapeutic approach allows ITA to accumulate in plaque and bone marrow, where it reduces inflammation and mimics the beneficial effects of LCLFD without requiring drastic lifestyle changes.

“We have already seen its effectiveness in multiple models of atherosclerosis,” Maiseyeu said. “We are optimistic that this will result in better treatments that will greatly lower the long-term risk of heart attacks and strokes while also improving patients’ quality of life.”

Maiseyeu and his team are now taking steps to translate ITA-LNP to the clinic, including engineering a pill form of the treatment, which they believe will not only be convenient for patients, but also transformative.

More information: Natalie E. Hong et al, Nanoparticle-based itaconate treatment recapitulates low-cholesterol/low-fat diet-induced atherosclerotic plaque resolution, Cell Reports (2024). DOI: 10.1016/j.celrep.2024.114911

Journal information: Cell Reports 

https://medicalxpress.com/news/2024-11-inflammation-molecule-atherosclerosis.html

Discovery reveals how low-dose ketamine, a ‘lifesaving’ drug for major depression, alleviates symptoms within hours

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by Ellen Goldbaum, University at Buffalo

University at Buffalo neuroscientists have identified the binding site of low-dose ketamine, providing critical insight into how the medication, often described as a wonder drug, alleviates symptoms of major depression in as little as a few hours with effects lasting for several days.

Published in Molecular Psychiatry, the UB discovery will also help scientists identify how depression originates in the brain, and will stimulate research into using ketamine and ketamine-like drugs for other brain disorders.

A lifesaving drug

Ketamine has been used since the 1960s as an anesthetic, but in 2000, the first trial of far lower doses of ketamine proved its rapid efficacy in treating major depression and suicidal ideation.

“Due to its fast and long-lasting effects, low-dose ketamine proved to be literally a lifesaving medicine,” says Gabriela K. Popescu, Ph.D., senior author on the research and professor of biochemistry in the Jacobs School of Medicine and Biomedical Sciences at UB.

Traditional antidepressants take months to kick in, which increases the risk for some patients to act on suicidal thoughts during the initial period of treatment. Ketamine provides almost instant relief from depressive symptoms and remains effective for several days and up to a week after administration. Since this observation was published in the early 2000s, ketamine clinics, where the drug is administered intravenously to treat depression, have been established in cities nationwide.

But just how ketamine achieves such a dramatic antidepressive effect so quickly has been poorly understood at the molecular level. This information is critical to understanding not only how best to use ketamine, but also to developing similar drugs.

Selective effects on NMDA receptors

Ketamine binds to a class of neurotransmitter receptors called N-methyl-D-aspartate (NMDA) receptors. Popescu is an expert on how these receptors produce electrical signals that are essential for cognition, learning and memory, and how these signals, when dysregulated, result in psychiatric symptoms.

“We demonstrate in this article how ketamine at very low concentrations can affect the activity of only select populations of NMDA receptors,” says Popescu

NMDA receptors are present throughout the brain and are essential for maintaining consciousness. For this reason, she explains, drugs that act indiscriminately on all NMDA receptors have unacceptable psychiatric side effects.

“We believe that the selectivity we uncovered in our research explains how low-dose ketamine can treat major depression and prevent suicides in people with depression,” Popescu says.

The research was sparked by an observation in her lab by co-author Sheila Gupta, then a UB undergraduate. “Sheila noticed that when applied onto NMDA receptors that were chronically active, ketamine had a stronger inhibitory effect than expected based on the literature,” Popescu explains. “We were curious about this discrepancy.”

Back when ketamine’s antidepressant effects first became known, researchers tried to find out how it worked by applying it onto synaptic currents produced by NMDA receptors, but the drug produced little or no effect.

“This observation caused many experts to turn their attention to receptors located outside synapses, which might be mediating ketamine’s antidepressive effects,” Popescu says.

“Sheila’s observation that ketamine is a stronger inhibitor of receptors that are active for longer durations inspired us to look for mechanisms other than the direct current block, which was assumed to be the only effect of ketamine on NMDA receptors.”

Few labs with this NMDA expertise

Popescu’s lab is among a handful in the world with the expertise to quantify the process by which NMDA receptors become active. This allowed Popescu and her colleagues to identify and measure what exactly changed during the NMDA activations when ketamine was present at very low doses versus when it was present at high (anesthetic) doses.

“Because we track activity from a single receptor molecule over an extended period of time, we can chart the entire behavioral repertoire of each receptor and can identify which part of the process is altered when the receptor binds a drug or when it harbors a mutation,” Popescu explains.

“The mechanism we uncovered suggests that at low doses, ketamine will only affect the current carried by receptors that had been active in the background for a while, but not by synaptic receptors, which experience only brief, intermittent activations,” she continues.

“This results in an immediate increase in excitatory transmission, which in turn lifts depressive symptoms. Moreover, the increase in excitation initiates the formation of new or stronger synapses, which serve to maintain higher excitatory levels even after ketamine has cleared from the body, thus accounting for the long-term relief observed in patients.”

The UB research helps explain why such low doses of ketamine are effective.

“Our results show that very low levels of ketamine, on the nanoscale, are sufficient to fill two lateral grooves of the NMDA receptors to selectively slow down extra-synaptic receptors, alleviating depression. Increasing the dose causes ketamine to spill over from the grooves into the pore and begin to block synaptic currents, initiating the anesthetic effect,” says Popescu.

Popescu’s co-authors in the Department of Physics in the College of Arts and Sciences simulated the three-dimensional structure of the NMDA receptor and predicted the exact residues to which ketamine binds in the lateral sites.

“These interactions are strong and account for the high affinity of the receptor for low doses of ketamine,” she says.

“The simulations show that at high concentrations, which is how it is used as an anesthetic, ketamine indeed lodges itself in the central ion-conducting pore of the receptors, where it stops ionic current from flowing through the receptor,” says Popescu.

In contrast, at low concentrations, ketamine functions very differently, attaching to two symmetrical sites on the sides of the pore, such that instead of stopping the current, ketamine makes receptors slower to open, reducing the current only a little bit.

“Finding the exact binding site on the receptor offers the perfect template for developing ketamine-like drugs that could be administered orally and may lack the addictive potential of ketamine,” says Popescu.

The natural next step is to screen existing drugs that can fit in the lateral grooves of NMDA receptors, first computationally and then experimentally.

More information: Jamie A. Abbott et al, Allosteric inhibition of NMDA receptors by low dose ketamine, Molecular Psychiatry (2024). DOI: 10.1038/s41380-024-02729-9

Journal information: Molecular Psychiatry 

https://medicalxpress.com/news/2024-11-discovery-reveals-dose-ketamine-lifesaving.html